tbuckley/cabot-search huggingface dataset:
EPID-02. ANTIBODY REACTIVITY TO VARICELLA-ZOSTER VIRUS AND THREE OTHER HERPESVIRUSES AND SURVIVAL IN ADULTS WITH GLIOMA
Authors: Geno Guerra, Stephen Francis, Lucie McCoy, Helen Hansen, Terri Rice, Annette Molinaro, John Wiencke, Margaret Wrensch
Journal: Neuro-Oncology (2022)

Abstract Measures of Varicella-Zoster virus (VZV) have been consistently inversely associated with glioma risk, but the association with glioma survival has not been investigated. In this study we analyzed overall survival of individuals with glioma in relation to measured levels of antibodies to 4 common viral infections, measured post-diagnosis. METHODS We utilized immunoglobulin G (IgG) antibody measurements to VZV, Epstein-Barr virus (EBV), herpes simplex virus (HSV), and cytomegalovirus (CMV), collected from 1378 patients newly enrolled in the UCSF Adult Glioma Study between 1991-2010. Blood was obtained a median of 3 months post diagnostic surgery. Subject follow-up for survival is ongoing. The associations of IgG levels with overall survival were estimated using Cox models adjusted for age, sex, race, type of surgery, dexamethasone usage, and stratified by tumor grade. RESULTS The 1378 glioma patients studied had median survival of 2.1 years. VZV antibody seropositivity was associated with improved survival outcomes (Hazard ratio, HR = 0.70, 95% Confidence Interval 0.54-0.90, p = 0.0061), with a grade-IV specific association (HR=0.65, 0.48-0.87, p=0.0046). Amongst VZV seropositive cases, those in the bottom quartile of measured seroreactivity had significantly worse survival outcomes as compared to the upper three quartiles (HR = 1.31, 1.13-1.52, p = 0.0003). Antibody seropositivity to EBV was also associated with improved survival times (HR = 0.71, 0.53-0.96, p = 0.028). Antibody response to two other common viruses (CMV, HSV) were not associated with glioma survival (p = 0.213, p = 0.215, respectively). CONCLUSION This is the first study, to our knowledge, to associate virus-specific antibody levels with survival amongst glioma patients. These associations do not appear to be due to general tumor-induce immune suppression. Our results controlled for dexamethasone usage, a known immunosuppressor. IgG measurements were taken post-glioma diagnosis, therefore further study is needed to determine the direction of causation, and if anti-herpesvirus treatment, such as VZV vaccination, might be beneficial for glioma prognosis.
EPCO-29. KLF5 IS REQUIRED FOR THE SEX-DIFFERENCES ACROSS MULTIPLE TUMORIGENIC PHENOTYPES IN PEDIATRIC GLIOBLASTOMA (GBM)
Authors: Tamara Abou-Antoun, Joshua Rubin, Rob Mitra, Najla Kfoury, Xuhua Chen, Nicole Warrington, India Reiss
Journal: Neuro-Oncology (2022)

Abstract High-grade glioblastoma (GBM) is a highly heterogeneous, malignant cancer with no cure to date. A sex-biased incidence and therapeutic response is reported (1) for GBM with a male to female incidence ratio of 1.6:1 and female patients having a 4-6 month survival advantage (2) compared to male patients. In our current work, we sought to determine the molecular basis for the sex-bias in incidence and therapeutic response using an isogenic murine model of GBM with dual loss of neurofibromin 1 (NF1) and P53 (DNP53) in astrocytes. Our model yielded GBM from the murine astrocytes in a sex-biased manner, with male GBM cells exhibiting a highly significant proliferative, migratory, in-vivo tumorigenicity, stem-cell enrichment rate and therapeutic resistance compared to female GBM cells. Using transposon calling cards, we mapped Brd4 enhancer usage across the genome in male, compared to female GBM cells and identified key transcription factors that differentially enriched at male-biased, compared to female-biased Brd4 bound enhancers. Interestingly, female-biased Brd4-bound enhancers were enriched for transcription factors with tumor suppressor roles including P53 and SMAD4, whereas male-biased Brd4-bound enhancers were enriched for transcription factors with oncogenic roles, including Oct4, MYC and KLF5. Genetic or chemical silencing of KLF5 reduced the tumorigenic potential in male GBM with rates of cellular proliferation, survival, migration and stem-cell frequency significantly reduced to levels that resemble female GBM. Using transposon calling cards, we mapped KLF5 genomic localization in male and female GBM cells and identified significant peaks that affiliated with differentially expressed genes between the sexes. Interestingly, genes induced by KLF5 in the male cells were affiliated with poor survival in patients with various cancers, whereas those induced by KLF5 in the female cells were affiliated with favorable prognosis. This signifies the need to explore molecular mechanisms by which KLF5 drives these sex differences in GBM.
ANGI-04. DEPLETION OF CHITINASE-3-LIKE PROTEIN 1 (CHI3L1) IN HUMAN U87-MG GLIOMA CELLS AFFECTS TUMOUR GROWTH AND NEOVASCULATURE IN INTRACRANIAL MOUSE MODEL
Authors: Salwador Cyranowski, Malgorzata Zawadzka, Bartosz Wojtas, Julian Swatler, Bozena Kaminska
Journal: Neuro-Oncology (2022)

Abstract Chitinase-3-like protein 1 (CHI3L1) plays multiple roles in inflammation, tissue remodelling, and wound healing. It is a new, potentially druggable target for the treatment of cancer due to its association with both extracellular matrix (ECM) modifications and potential involvement in neoangiogenesis. Expression of CHI3L1 is upregulated in glioblastoma (GBM), the most common and aggressive primary brain tumour. The role of CHI3L1 in GBM progression is not fully understood and calls for further research. We generated a knockout (KO) of CHI3L1 in human glioblastoma U87-MG cells. To evaluate the effects of CHI3L1 KO on tumour growth, wild-type (WT) or CHI3L1 KO cells were intracranially implanted into athymic mice and tumour volume was assessed with magnetic resonance imaging. We have measured the serum level of CHI3L1 in both groups and correlated it with the tumour burden. Immunofluorescent staining against endothelium marker – von Willebrand factor (vWF), and perivascular water channel – aquaporin 4 (AQP4) were employed to evaluate the tumour vasculature in both groups. We found that CHI3L1 KO in glioblastoma cells significantly reduced volume of established tumors. Blood serum level of CHI3L1 positively correlated with tumour burden of experimental animals, which corroborates its role as a biomarker. Immunostaining for vWF revealed that in CHI3L1 KO gliomas there were more non-capillary blood vessels than in controls. We observed a higher level of AQP4 in CHI3L1 KO tumours, which suggests a difference in the structure of perivascular space, and thus vasculature functionality, in CHI3L1 depleted gliomas. In conclusion, we demonstrated the involvement of glioma-derived CHI3L1 in the growth and neovasculature of experimental human gliomas. Our findings suggest that the depletion of CHI3L1 in glioma cells results in a higher number and possibly different structure of non-capillary blood vessels in the tumour. Studies supported by the grant N 2020/39/B/NZ4/02683 from the National Science Center.
EPCO-48. STEMNESS SIGNATURE STRATIFIES GLIOMAS WITH CLINICAL IMPORTANCE AND REVEALS A PROLIFERATIVE PHENOTYPE IN SINGLE CELL DATA
Authors: Renan Simões, Maycon Marção, Tathiane Malta
Journal: Neuro-Oncology (2022)

Abstract Gliomas are the most common central nervous system neoplasm and despite the past significant progress, its diagnostics faces suboptimal classification which impacts patient management. The stem cell-like phenotype of various cancers is correlated with the worst overall prognosis. We propose a Stemness prediction model based on gene expression signatures of neural progenitors that can be used to measure the dedifferentiation state (or Stemness) of glioma samples. To built the model, publicly available single-cell RNA sequencing data was used to identify gene expression from the fetal astrocyte (AST) population. Subpopulations of interest were identified through the expression of marker genes. We applied a one-class logistic regression to built the prediction model using the AST population. The model was applied to glioma bulk transcriptomic data to generate an fetal astrocyte stemness index (ASTsi). The ASTsi was able to stratify gliomas based on grade, histology, and molecular subtypes. Grade 4, glioblastoma, IDHwt, and the mitochondrial and proliferative functional subtypes had the highest stemness. When applied to longitudinal samples we observed an increase of ASTsi in IDHmut recurrent and a decrease in IDHwt recurrent tumors, compared to primary samples. Additionally, we applied the model to single-cell RNAseq of adult IDHwt glioblastomas and found clusters of high-stemness cells (ASTsi &amp;gt; 0.8). A differential gene expression combined with pathway analysis between high- and low-stemness cells revealed cell cycle, DNA repair mechanisms and histone modifications upregulated in the high-stemness population. The balance between histone methylation and demethylation may be directly related to the phenotype of these cells. More in-depth analysis of these genes and pathways are being carried out and may provide important information about the oncogenesis and phenotypic characterization of glioma stemness. Our stemness prediction model stratified glioma samples by pathological and molecular features and revealed tumor subpopulations with distinct stemness degree in gliomas IDHwt.
EPCO-38. TYPE B ULTRA LONG-RANGE INTERACTIONS IN PFAS (TULIPS) ARE RECURRENT EPIGENOMIC FEATURES OF PFA EPENDYMOMA
Authors: Michael Johnston, John J Y Lee, Bo Hu, Ana Nikolic, Audrey Baguette, Seungil Paik, Haifen Chen, Sachin Kumar, Carol Chen, Selin Jessa, Polina Balin, Vernon Fong, Melissa Zwaig, Kulandaimanuvel MichealRaj, Xun Chen, Yanlin Zhang, Srinidhi Varadharajan, Pierre Billon, Nikoleta Juretic, Craig Daniels, Caterina Giannini, Eric Thompson, Peter Hauser, Seung-Ki Kim, Kyu-Chang Wang, Ji Yeoun Lee, Wieslawa Grajkowska, Sameer Agnihotri, Stephen C Mack, Benjamin Ellezam, Alex Weil, Guillaume Bourque, Jennifer Chan, Mathieu Lupien, Jiannis Ragoussis, Claudia Kleinman, Jacek Majewski, Nada Jabado, Michael Taylor, Mathieu Blanchette, Marco Gallo
Journal: Neuro-Oncology (2022)

Abstract Posterior Fossa Group A (PFA) ependymomas are pediatric brain tumors with extremely poor survival outcomes. As protein-coding mutations in PFA are exceedingly rare, the underlying etiology of these tumors remains elusive. Elevated CpG island methylation and depletion of H3K27me3 have been described in PFA, leading to the hypothesis that PFA may be driven by a dysregulated epigenetic state. In this study, we sought to determine how three-dimensional (3D) genome features (such as DNA loops, domains, and compartments) differ between pediatric brain tumors. We performed Hi-C sequencing on a collection of 64 patient specimens and patient-derived primary cultures that collectively span multiple subgroups of ependymoma, medulloblastoma, high-grade glioma, and non-neoplastic brain. For certain samples, we further performed RNA-seq, histone modification ChIP-seq, or whole-genome bisulfite sequencing to allow multiomic data integration. Overall, the 3D genome organization of PFA samples appeared distinct from other tumor types. We identified and defined TULIPs: a subset of type B compartments, separated by genomic distances greater than 10 Mbp, that exhibit a striking fivefold increase in reciprocal interaction strength. These TULIPs recurred at the same genomic positions across the vast majority of PFA samples with minimal representation among other tumor or non-tumor samples. TULIPs displayed enrichment for heterochromatic features such as H3K9me3 and late replication timing and were depleted of euchromatic features such as H3K27ac and protein-coding genes. By using immuno-fluorescence for H3K9me3 and oligo-FISH to label TULIP regions, we demonstrated that TULIP regions are more compact in PFA than other tumors. Finally, by applying inhibitors of H3K9 lysine methylation to PFA cultures we showed that TULIPs become more diffuse and cell viability is reduced. Altogether, this work defines TULIPs as highly recurrent epigenetic features of PFA tumors.
IMMU-04. SINGLE-CELL RNA-SEQUENCING IDENTIFIES FUNCTIONAL MACROPHAGE SUBSETS THAT ARE ENRICHED IN RESPONSE TO DIFFERENTIAL PHAGOCYTOSIS INDUCTION AGAINST GLIOMA
Authors: Senthil Lakshmana Chetty, Kent Riemondy, Andrew Donson, Ilango Balaakrishnan, Sujatha Venkataraman, Rajeev Vibhakar, Nicholas Foreman, Siddhartha Mitra
Journal: Neuro-Oncology (2022)

Abstract Pediatric diffuse midline gliomas (DMGs), are fatal brain tumors of childhood arising in the ventral pons. Currently, radiation therapy (RT) is the mainstay treatment for DIPG. However, RT is not a curative treatment and provides only temporary relief for most patients. Recent advances in immunotherapy have yielded some fantastic opportunities to effectively treat patients with high-grade pediatric brain tumors. In this study, we demonstrate that fractionated RT (4Gy X 3) induces immunogenic cell death and activates multiple damage-associated molecular patterns (DAMPs) on DMG/DIPG cells. Furthermore, combining 4Gy X 3 with anti-CD47 therapy enhances the in vitro phagocytosis of DIPG/DMG cells by peripheral blood mononuclear cell-derived macrophages. Next, using single-cell RNA sequencing (scRNA-seq), we investigated the transcriptomic profile of macrophages that were co-cultured with irradiated or non-irradiated DMG cells in the presence of either phosphate-buffered solution (PBS) or anti-CD47 monoclonal antibody for 24 hours. Our findings identified eleven distinct macrophage clusters displaying different gene expression patterns in all the treatment conditions. However, PBS treatment led to a marked increase in macrophages expressing antigen-presentation genes (HLA-DR and HLA-DQB1). 4Gy X 3 treatment led to the enrichment of macrophages expressing genes related to the oxidative phosphorylation pathway, whereas anti-CD47 treatment led to the enrichment of macrophages expressing genes related to interferon-gamma response and ERK-signaling pathway. Lastly, mice intracranially transplanted with DMG/DIPG that received 4Gy X 3 and anti-CD47 therapy showed a significant decrease in tumor growth and an increase in survival rate than those receiving either monotherapy alone. We are currently performing scRNA-seq validation studies on tumors obtained from orthotopic and syngeneic models of DMG. In summary, our results highlight the functional heterogeneity of macrophages and suggest that combining fractionated RT with anti-CD47 therapy has potent anti-tumor effects and may be used as a novel therapeutic approach for treating Glioma patients.
IMMU-11. NONO IS A NEW ADENOVIRUS SENSOR: IMPLICATION FOR VIROTHERAPY
Authors: Andrew Gillard, Dong Ho Shin, Virginia Laspidea, Sanjay K Singh, Hong Jiang, Debora Kim, Xuejun Fan, Yanhua Yi, Frederick Lang, Marta M Alonso, Juan Fueyo, Candelaria Gomez-Manzano
Journal: Neuro-Oncology (2022)

Abstract The median survival for GBM patients is 15 months with a five-year survival rate of less than 10%. Current conventional and experimental treatments, including immune checkpoint blockade, have not improved outcomes in the vast majority of glioma patients. Oncolytic viruses (OVs) are designed to specifically infect and lyse cancer cells to elicit an anti-tumor immune response. In a clinical trial developed by the MDACC team, 20% of GBM patients treated with the oncolytic adenovirus Delta-24-RGD showed complete response and survival longer than three years (NCT00805376). Although these studies have shown that robust immune responses can be invoked using oncolytic virotherapy, the molecular mechanisms underlying OV-mediated anti-tumor immunity remain elusive. Exposure to viruses by innate immune sensors induces protective antiviral immunity. Using bulk RNA sequencing of cells infected with adenovirus we identified the main upstream regulators of the innate immune response including IFN gamma, Interferon responsive genes 3 and 7, and STAT3. However, RNAseq unexpectedly uncovered NONO (Non-POU Domain Containing Octamer Binding) as the most relevant upstream regulator. In agreement with the RNAseq data, Protein analyses demonstrated the upregulation of NONO after adenovirus infection. In addition, immunofluorescence and confocal microscopy examination of the infected cells showed the overexpression and translocation to the nucleus of NONO upon virus infection. We are the first laboratory that has identified NONO as a sensor of adenovirus infection, which may have great significance for the future development of oncolytic viruses. Importantly, we discovered the network of proteins that are upregulated after NONO activation and, finally, we have established that changes in the expression level and subcellular localization of NONO are coincident in time during the infection of cultured cells. Future work is focused on examining the immunomodulatory functions of NONO in adenoviral infected tumors and subsequent generation of NONO-resistant oncolytic adenovirus.
EPID-25. THE CLINICAL AND MOLECULAR LANDSCAPE OF GLIOMAS IN ADOLESCENTS AND YOUNG ADULTS
Authors: Julie Bennett, Liana Nobre, Javal Sheth, Scott Ryall, Karen Fang, Monique Johnson, Logine Negm, Jiil Chung, Martin Komosa, Nuno Nunes, Mary Jane Lim-Fat, James Perry, Arjun Sahgal, Jay Detsky, Eric Bouffet, Lili-Naz Hazrati, Peter Dirks, Birgit Ertl-Wagner, Paul Kongkham, Gelareh Zadeh, Warren Mason, Michael Cusimano, Sunit Das, Andrew Gao, Derek Tsang, Lananh Nguyen, Normand Laperriere, Julia Keith, David Munoz, Uri Tabori, Cynthia Hawkins
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE Gliomas in adolescents and young adults (AYA) are commonly treated with a standard chemo-radiation approach. Molecular alterations have not been comprehensively described to date. METHODS We compiled a multi-institutional cohort of patients diagnosed with glioma between 15-39.9 years over 20 years. Molecular analysis, therapeutic data and outcome was collected. For specific alterations, analysis included patients aged 0-39.9 years. RESULTS A total of 1900 patients with 876 AYA gliomas were included. Ongoing analysis reveals genetic alterations in 95% of available tumours. IDH p.R132H was found in 49% of tumours, while non-canonical IDH mutations were found in 7%. Paediatric-type mutations were found in 33% of AYA tumours with IDH-WT GBM accounting for the remaining 11%. The most common paediatric alterations in AYAs included BRAF p.V600E (11%) and FGFR alterations (7%) while BRAF fusions, H3 p.K27M and H3.3 p.G34R were rarely observed (4%, 4% and 1% respectively). BRAF fused tumours with non-canonical binding partners were enriched in AYAs. Analysis of BRAF-V600E gliomas between ages 0-40 revealed increased tendency for malignant tumours in patients &amp;gt; 20 years suggesting malignant transformation possibly due to higher rate of secondary hits. This resulted in worse overall-survival for AYA patients with BRAF-V600E glioma when compared to children under 20 years (p=0.0032). Ten-year OS of 100%, 90% and 95% was seen for BRAF fused, BRAF-V600E and FGFR-altered AYA low grade glioma respectively, compared to 14% and 25% for BRAF-V600E and FGFR-altered high grade glioma. In contrast, continuous decline was observed in the IDH-mutant gliomas with 10-year OS of 50% which declined to 29% at 15 years. CONCLUSIONS Gliomas in AYA often have non-canonical alterations that may evade standard molecular analysis. They are enriched for paediatric-type alterations with distinct molecularly-based outcomes. These tumours may respond to targeted inhibitors and would benefit from comprehensive diagnostic and therapeutic approaches.
EPID-12. REGIONAL VARIATIONS IN THE INCIDENCE OF BRAIN GLIOMA IN ADULTS IN ALABAMA
Authors: Mina Lobbous, Moaaz Abdelrashid, Dagoberto Estevez-Ordonez, James Markert, Meghan Tipre, Elizabeth Brown, Louis Nabors, Cora Lewis
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Gliomas are the most common primary brain tumor in adults in the US with an annual age-adjusted incidence rate (AAA-IR) of 4.67 to 5.73 per 100,000 persons. There are several sources of carcinogenic contaminants in northeast Alabama and western Georgia with the Coosa River serving as the region’s primary water source. We aimed to examine the incidence rate of glioma, as well as tumor characteristics and overall survival, in northeast Alabama compared to the rest of the state. METHODS This is a retrospective cohort study using the UAB Neuro-Oncology clinic database including adult patients ( ≥ 20 years at diagnosis) with histologically confirmed diagnosis of glioma (ICD10: 71.9) residing in the state of Alabama at the time of diagnosis between January 2015 and December 2019. We calculated AAA-IR among residents in counties intersected by the Coosa River in northeast Alabama (exposed group) compared to the rest of the state (non-exposed group). The electronic medical records of the participants were reviewed for patient demographics, insurance status, tumor grade and molecular markers, as well as the vital status. The overall survival was graphically examined using Kaplan-Meier. RESULTS A total of 660 patients were included in this study (528 non-exposed, and 132 exposed). The AAA-IR of glioma in the exposed group was 4.76 per 100,000 persons vs 3.14 per 100,000 persons in the non-exposed group with a 50 % higher incidence rate of glioma in the exposed group (RR = 1.50; 95% CI, 1.22-1.89). There was no statistically significant difference between the two groups with respect to age at diagnosis, sex, race, surgery type, tumor grade, IDH status, or overall survival. CONCLUSIONS Our findings indicate a higher incidence of glioma in northeast Alabama. Future geospatial and population-based epidemiological investigations are needed to identify possible regional environmental risk factors and examine temporal sequence.
EPID-19. CHANGES IN SURVIVAL OVER TIME FOR ALL PRIMARY BRAIN AND OTHER CNS TUMORS IN THE UNITED STATES
Authors: Jacob Edelson, Kristin Waite, Gino Cioffi, Carol Kruchko, Quinn Ostrom, Jill Barnholtz-Sloan
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Despite advances in cancer diagnosis and clinical care, survival for many primary brain and other central nervous system (CNS) tumors remain poor. This study performs a comprehensive survival analysis on these tumors. METHODS Survival differences were determined utilizing the National Program of Cancer Registries Survival Analytic file for all primary brain and other CNS tumors. Overall survival and survival of the 5 most common histopathologies within specific age groups (children ages 0-14 years, adolescents, and young adults [AYA] ages 15-39 years, and older adults ages 40+ years) were determined. Overall survival was compared for three time periods: 2004-2007, 2008-2012, and 2013-2017. Kaplan-Meier and multivariable Cox proportional hazards models were used to generate median survival, hazard ratios (HR) and 95% confidence intervals (CI). Models were adjusted for sex, race/ethnicity, and treatment pattern. Malignant and non-malignant brain tumors were assessed separately. RESULTS Aside from hemangioma and mesenchymal tumors in older adults, no notable changes in survival were observed across the time periods for non-malignant tumors. For malignant brain tumors, significant survival improvements were observed in children with embryonal tumors (logrank p = 0.00028) and in AYA with anaplastic astrocytoma (logrank p = 0.0043). In older adults, significant improvement was observed in the five most common histopathologies except oligodendroglioma. Adjusted for sex, race/ethnicity, and treatment, there were improvements in survival in 2008-2012 and 2013-2017, when compared to 2004-2007, in children and AYA with malignant tumors (Children: HR = 0.92, 95% CI = 0.87-0.98, p = 0.010 in 2008-2012; HR = 0.91, 95% CI = 0.85-0.97, p = 0.005 in 2013-2017; AYA: HR = 0.92, 95% CI = 0.88-0.96, p &amp;lt; 0.001, in 2008-2012; HR = 0.87, 95% CI = 0.83-0.93, p &amp;lt; 0.001 in 2013-2017). CONCLUSIONS Overall survival for malignant brain and other CNS tumors improved slightly in 2013-2017 for all age groups as compared to 2004-2007. No significant changes were observed for non-malignant brain and other CNS tumors.